Interactions between the gut microbiome and the immune system have been linked to inflammatory bowel disease (IBD). IBD is a chronic and progressive gastrointestinal disease characterized by uncontrolled activation of the intestinal immune system resulting in severe medical complications, affecting over 1.5 million patients in the United States. It is a disease of high unmet medical need, currently treatable with only one of twelve approved immunosuppressive therapies, often leading to toxic side effects. Symbiotix Biotherapies, Inc. is an early-stage biotechnology company developing a first-in-class therapeutic agent for IBD and other immune-mediated diseases based on recent discoveries emerging from the human microbiome. Our scientific founders have identified a specific gut commensal organism, Bacteroides fragilis, that induces interleukin (IL)- 10-secreting regulatory T cells (Tregs) that are able to dampen the pro-inflammatory activities of Th1, Th2 and Th17 subsets of T cells. We have furthermore identified a specific capsular polysaccharide (PSA) from this organism responsible for the protective effect, shown that PSA works through a novel mechanism of Treg activation to expand anti-inflammatory T cell populations in mice, and shown that oral administration of purified PSA is protective in multiple models of mouse colitis. Our objective for this Phase 2 STTR project is to conduct key translational activities that will be essential for advancing PSA towards an IND filing as a safe and efficacious oral first-in-class treatment for human inflammatory bowel disease. The project consists of 3 Specific Aims: In Specific Aim 1, we will expand on initial human in vitro efficacy studies that demonstrate the capacity of PSA to convert nave T cells into Treg cells in culture that secrete anti-inflammatory IL-10, to evaluate the effect of PSA on PBMCs and gut tissue taken from patients with inflammatory bowel disease. In Specific Aim 2, we will work with a biopharmaceutical contract manufacturer to scale up the manufacturing process that we have optimized to enable production of 200L batches that can support IND-enabling GLP toxicology studies. In Specific Aim 3, we will carry out analytical method development to support scaleup and production of larger quantities of material necessary for tox studies and clinical trials. These Specific Aims will lay the essential groundwork allowing PSA to move to IND filing and Phase I clinical trial. As our company works to translate the groundbreaking academic studies that have resulted in the first therapeutic molecule to emerge from the human microbiome, Phase 2 STTR support will advance this revolutionary treatment option for IBD to the brink of human clinical trials, and will pave the way for application of PSA to other immune- mediated diseases such as multiple sclerosis, asthma and rheumatoid arthritis.